EP0111151A1 - Composés de nitropyrazine substitués, procédé pour leur préparation et compositions pharmaceutiques les contenant - Google Patents

Composés de nitropyrazine substitués, procédé pour leur préparation et compositions pharmaceutiques les contenant Download PDF

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Publication number
EP0111151A1
EP0111151A1 EP83110974A EP83110974A EP0111151A1 EP 0111151 A1 EP0111151 A1 EP 0111151A1 EP 83110974 A EP83110974 A EP 83110974A EP 83110974 A EP83110974 A EP 83110974A EP 0111151 A1 EP0111151 A1 EP 0111151A1
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EP
European Patent Office
Prior art keywords
formula
nitropyrazine
hydrogen
group
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP83110974A
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German (de)
English (en)
Other versions
EP0111151B1 (fr
Inventor
George D. Hartmann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
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Filing date
Publication date
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP0111151A1 publication Critical patent/EP0111151A1/fr
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Publication of EP0111151B1 publication Critical patent/EP0111151B1/fr
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms

Definitions

  • Substituted nitropyrazine compounds process for their preparation and pharmaceutical compositions containing them.
  • This invention relates to 2 and/or 6 substituted 3-nitropyrazine compounds used as sensitizers of tumor cells to therapeutic radiation. It also relates to the process of preparing such compounds starting with chloroaminopyrazines, converting said chloroaminopyrazines to the corresponding chloronitropyrazines and aminating said chloronitropyrazines to produce the substituted nitropyrazines useful in the sensitization qf tumor cells to the therapeutic effect of radiation.
  • compositions of the present invention are nitropyrazine compounds of the formula wherein R and R 1 are each selected from the group consisting of
  • compositions of the present invention that are particularly useful as radiation sensitizers are nitropyrazine compounds of the formula wherein R and R 1 are each selected from the group consisting of
  • the reagent is prepared by mixing dimethylsulfoxide in methylene chloride and cooled to -78°C. To the cooled solution is added trifluoromethane sulfonic anhydride in a ratio of approximately 3 moles dimethylsulfoxide to 2 moles of anhydride to produce dimethyl sulfide ditriflate of the formula
  • the product is then oxidized while maintaining the temperature at or below 0°C preferably using an organic peroxy carboxylic acid e.g., m-chloroperbenzoic acid as the oxidizing agent to produce the desired nitropyrazine of formula V.
  • an organic peroxy carboxylic acid e.g., m-chloroperbenzoic acid
  • compounds of formula V wherein R 4 or R 5 is halogen are then treated with ammonia or an hydroxyalkylamine or an alkoxyalkylamine of the formula wherein R 2 and R 3 are as defined hereinabove to produce a nitropyrazine of the formula wherein at least one of R and R 1 is NR 2 R 3 as defined hereinabove and the other of R and R 1 is defined as hydrogen or carboalkoxy in which the alkoxy group contains from 1-3 carbons.
  • the method of treatment of human patients or domestic animals undergoing radiation treatment of malignant disease processes employs the compounds of the present invention in pharmaceutical compositions that are administered orally or parenterally, or intravenously.
  • the dose employed depends on the radiation protocol for each individual patient. In protocols where the radiation dose is divided into a large number, of fractions, the drug can be administered at intervals in the schedule and not necessarily with each radiation treatment. It should be noted that the compounds of the present invention are not intended for chronic administration.
  • the drug is administered from 10 minutes to 5 hours prior to the radiation treatment in a dosage amount of between 0.25 to about 4.0 grams per square meter of body surface approximately equivalent to a dosage of 6 to 100 mg/kg of patient body weight as set forth in the "Nelson Textbook of Pediatrics" Eleventh Edition (1979) p. 31, edited by Vaughan, M cKay, Behrman, and Nelson.
  • the dosage range given is the effective dosage range and the decision as to the exact dosage used must be made by the administering physician based on his judgement of the patient's general physical condition. In determining the dose for the individual patient, the physician may begin with an initial dose of 0.25 g/square meter of body surface to determine how well the drug is tolerated and increase the dosage with each suceeding radiation treatment, observing the patient carefully for any drug side effect.
  • the composition to be administered is an effective amount of the active compound and a pharmaceutical carrier for said active compound.
  • the dosage form for intravenous administration is a sterile isotonic solution of the drug.
  • Oral dosage forms such as tablets, capsules, or elixirs are preferred.
  • Capsules or tablets containing 25, 50, 100 or 500 mg of drug/capsule or tablets are satisfactory for use in the method of treatment of our invention.
  • Step A S,S-Dimethyl-N-(3-chloropyrazin-2-yl)sulfilimine (2)
  • reaction mixture is then quenched with 50 ml of 5% aqueous sodium bicarbonate solution and stirred at -5° for 5 minutes.
  • the reaction mixture is diluted with 200 ml methylene chloride and the phases are separated.
  • the aqueous phase is extracted with 250 ml methylene chloride and the combined organic phases are washed with 3 x 75 ml portions of water and dried over anhydrous sodium sulfate.
  • the solvent is removed from the rotary evaporator to give 5.8 g (79%) of 2 as yellow crystals, m.p. 106-108°.
  • the resulting suspension is extracted with 2 x 50 ml saturated sodium bicarbonate and the organic phase is dried over anhydrous sodium sulfate.
  • the solvent is removed from the rotary evaporator to give a yellow oil which is purified by flash chromatography on silica gel with chloroform elution. Pure 3 is a pungent, yellow oil.
  • Step A S,S-Dimethyl-N-(5-chloropyrazin-2-yl)sulfilimine (5)
  • Compound 5 is prepared from 2-amino-5-chloropyrazine as described above for 2 in Example lA to afford pure 5 as a smelly, tan solid, m.p. 119-120°.
  • Step A S,S-Dimethyl-N-(5-chloro-3-methoxycarbonyl- pyrazin-2-yl)sulfilimine (8)
  • Compound 8 is prepared from methyl 6-chloro-3-aminopyrazinoate (7) as described in Example lA for 2, to afford crude 8 which is recrystallized from methylene chloride/hexane. Pure 8 is obtained as a yellow solid, m.p. 167-9°.
  • Compound 9 is prepared from 8 as described in Example 1B for 3, to give crude 9 which is purified by flash chromatography on silica gel eluting with 2% methanol/chloroform. Pure 9 is a pungent yellow oil.
  • a pressure reactor is charged with 10.Og of 1,4-butane-2,3-epoxide, 30 ml liquid ammonia and 100 ml EtOH.
  • the reaction vessel is sealed and heated at 100° for 10 hrs.
  • reaction mixture is then stripped on the rotary evaporator to leave a clear, oil which is triturated with ether to afford the desired product as a viscous oil.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP83110974A 1982-11-12 1983-11-03 Composés de nitropyrazine substitués, procédé pour leur préparation et compositions pharmaceutiques les contenant Expired EP0111151B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US44120382A 1982-11-12 1982-11-12
US441203 1982-11-12

Publications (2)

Publication Number Publication Date
EP0111151A1 true EP0111151A1 (fr) 1984-06-20
EP0111151B1 EP0111151B1 (fr) 1987-12-09

Family

ID=23751951

Family Applications (1)

Application Number Title Priority Date Filing Date
EP83110974A Expired EP0111151B1 (fr) 1982-11-12 1983-11-03 Composés de nitropyrazine substitués, procédé pour leur préparation et compositions pharmaceutiques les contenant

Country Status (3)

Country Link
EP (1) EP0111151B1 (fr)
JP (1) JPS59101471A (fr)
DE (1) DE3374863D1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4892951A (en) * 1985-03-27 1990-01-09 Merck & Co., Inc. Derivatives of 3-nitropyridines useful as adjuncts to radiation therapy
CN100390153C (zh) * 2000-02-16 2008-05-28 富山化学工业株式会社 用于制备吡嗪衍生物的中间体

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3660397A (en) * 1970-04-17 1972-05-02 Merck & Co Inc Imidazo(4 5-b)pyrazines

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3660397A (en) * 1970-04-17 1972-05-02 Merck & Co Inc Imidazo(4 5-b)pyrazines

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4892951A (en) * 1985-03-27 1990-01-09 Merck & Co., Inc. Derivatives of 3-nitropyridines useful as adjuncts to radiation therapy
CN100390153C (zh) * 2000-02-16 2008-05-28 富山化学工业株式会社 用于制备吡嗪衍生物的中间体

Also Published As

Publication number Publication date
DE3374863D1 (en) 1988-01-21
JPS59101471A (ja) 1984-06-12
EP0111151B1 (fr) 1987-12-09

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